Hesperidin mitigates DEHP-induced nephrotoxicity through anti-oxidant, anti-apoptotic, and anti-inflammatory pathway modulation: Evidence from Nrf2/HO-1/Keap-1, Bax/Bcl-2/caspase-3, and TLR4/NF-κB axis activation
2026· Iranian Journal of Basic Medical Sciences· Vol 29, pp. 942 - 951· 0 citations· 21 references
Medicine
TL;DR
The protective mechanism involves anti-oxidant enhancement and inhibition of oxidative stress-induced inflammation and apoptosis, supporting the therapeutic potential of HSP in managing phthalate-related renal injury.
Abstract
Objective(s): This study aimed to assess the protective role of hesperidin (HSP), a citrus flavonoid, against di-(2-ethylhexyl) phthalate (DEHP)-induced kidney toxicity in rats, focusing on oxidative stress, apoptosis, inflammation, and anti-oxidant defense pathways. Materials and Methods: Thirty-five male rats were randomly assigned into five groups (7 per group): control group, DEHP-treated group (1 g/kg), DEHP + HSP (100 mg/kg) group, DEHP + HSP (200 mg/kg) group, and HSP-alone group, and treated orally for 10 consecutive days. Kidney tissues were collected for biochemical assays, including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Gene expression of Nrf2, Keap1, HO-1, Bax, Bcl-2, Caspase-3, TLR-4, and NF-κB was analyzed using real-time PCR, and protein levels were evaluated using Western blotting. Results: DEHP significantly increased oxidative damage and the expression of inflammatory and apoptotic markers, while decreasing anti-oxidant parameters. Co-treatment with HSP, particularly at 200 mg/kg, restored anti-oxidant balance, reduced lipid peroxidation, and down-regulated the expression of TLR-4, NF-κB, and Caspase-3. Moreover, HSP increased Bcl-2 levels and enhanced Nrf2/HO-1 signaling, as confirmed by both gene and protein expression data. Conclusion: HSP demonstrates dose-dependent renoprotective effects against DEHP-induced nephrotoxicity in rats. The protective mechanism involves anti-oxidant enhancement and inhibition of oxidative stress-induced inflammation and apoptosis, supporting the therapeutic potential of HSP in managing phthalate-related renal injury.
Cyclophosphamide (Cyclo) is an effective chemotherapeutic agent, but its clinical use is limited by severe cardiotoxicity driven by oxidative stress, inflammation, and apoptosis. Natural antioxidants such as carnosic acid (CA) may offer protection. This study aimed to investigate the protective effects of CA against Cyclo-induced cardiotoxicity in rats and to elucidate the underlying molecular mechanisms. Forty male Wistar rats were divided into four groups: control, CA alone, Cyclo alone, and Cyclo + CA. CA was administered orally at 100 mg/kg for 14 days, while Cyclo was injected intraperitoneally at 100 mg/kg on day 14. Cardiac injury was assessed using serum biomarkers, histology, immunohistochemistry (NF-κB, TNF-α, IL-1β, caspase-3), RT-PCR (Keap-1, Nrf2, HO-1, Bax, Bcl-2), and oxidative stress markers. Cyclo significantly elevated serum cardiac injury markers (CK, troponin, and LDH), as well as hepatic injury markers (ALT and AST), and induced severe histopathological damage, including leukocytic infiltration, congestion, edema, and fibrosis. Mechanistically, Cyclo suppressed the Keap1/Nrf2/HO-1 pathway by downregulating Nrf2 and HO-1 while upregulating Keap-1. Cyclo also depleted antioxidant enzyme activities (SOD, GPx, CAT), increased lipid peroxidation (MDA), activated NF-κB-driven pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted apoptosis via upregulation of Bax and caspase-3 alongside downregulation of Bcl-2. Co-treatment with CA markedly reversed all these pathological changes, restoring antioxidant and Nrf2/HO-1 signaling, reducing inflammatory markers, inhibiting apoptosis, and improving cardiac histology. CA effectively attenuates Cyclo-induced cardiotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These protective effects are likely associated with modulation of the Keap-1/Nrf2/HO-1 and NF-κB signaling pathways, highlighting CA’s therapeutic potential as a natural cardioprotective agent in chemotherapy-associated cardiac injury. Proposed schematic representation of the cardioprotective mechanism of CA against Cyclo-induced cardiotoxicity based on the present findings and previously published literature. Cyclophosphamide exposure leads to cardiac damage through the induction of oxidative stress, inflammation (NF-κB-mediated), and disorganization of cardiac histology, ultimately resulting in cardiotoxicity. Carnosic Acid mitigates this damage by activating the KEAP-1/NRF2/HO-1 pathway. This activation inhibits cytosolic Nrf2 degradation, allowing it to translocate to the nucleus and activate the Antioxidant Response Element (ARE). Concurrently, CA inhibits the NF-κB cascade, reducing the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). The combined effect is a reduction in oxidative stress (↓ROS, ↓MDA), inflammation, and apoptosis (as indicated by modulated Bax, Bcl-2, and Caspase-3), leading to decreased serum injury markers (CK, LDH, Troponin, AST, ALT, MDA), improved cardiac histology, and mitigation of cardiotoxicity.
Basma Salah, A. Abdelmonsef, Medhat Taha et al.· Bratislava Medical Journal· 0 citations
This study aimed to investigate the effect of hesperidin (HSP) at two different doses on deltamethrin (DLM)-induced testicular damage. The study comprised four groups of Wistar Albino rats (n = 8 per group): Control, DLM, DLM + HSP 100 mg/kg, and DLM + HSP 300 mg/kg. At the end of the study, oxidative stress markers and CRP were measured in serum samples. Testicular tissues were assessed histopathologically. Expression of Bcl-2, Bax, and Nrf-2 were determined by immunofluorescence staining. RT-qPCR assessed tissue collagen (COL1A1, COL3A1) and apoptotic () expressions. HSP at both doses lowered the DLM-induced increase in total oxidant status, oxidative stress index (total oxidant status/total antioxidant capacity), and CRP levels. Nrf-2 was increased by a high dose of HSP (300 mg/kg). Whereas HSP normalized other apoptotic parameters at both doses, it partially normalized Bax expression in immunofluorescence and Bcl-2 expression in RT-qPCR only at 300 mg/kg. HSP reduced the increased fibrosis in DLM exposure, as revealed by the expressions of COL1A1 and COL3A1 at both doses. HSP partially ameliorated DLM-associated histological alterations, including Johnsen’s score, tubule diameter, and thickness of the tunica albuginea. HSP may exert protective effects against DLM-induced testicular injury by modulating systemic oxidative status, apoptosis-associated signaling, and profibrotic gene expression.
The antioxidant, anti-inflammatory, anti-apoptotic, and Nrf2-pathway-modulating properties of quinic acid markedly attenuate cisplatin-induced acute kidney injury in rats and its impact on the associated oxidative, inflammatory, apoptotic, and Nrf2/HO-1/NQO1 pathways.
Mehdi Goudarzi, Z. Lamoochi, Susan Sabbagh et al.· Immunopharmacology and immun...· 1 citation
N-Cur mitigates oxidative damage and inflammation, thereby preserving hepatic function during CDDP-based chemotherapy, and demonstrates significant potential as a hepatoprotective agent when administered concomitantly with CDDP chemotherapy.
Q. Alqahtani, M. Atteya, T. Almatrafi et al.· Biomedicines· 0 citations
Doxorubicin (DOX) is an anticancer antibiotic that is widely utilized. Nevertheless, this therapeutic potential is hampered by its cardiotoxicity. Alogliptin (ALO), an antidiabetic, recently is being repurposed for the management of various organs ailments owing to its discovered biological activities as an antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic through multiple pathways. This study is directed to evaluate the possible protective effect of ALO against DOX-induced cardiac molecular and histopathological alterations. Twenty-four adult Wistar rats were grouped into control in addition to ALO (20 mg/kg, p.o, 21 days), DOX (18 mg/kg, i.p; six equal divided doses on alternative days starting at day 8), and Dox + ALO treated groups. On the 21st day, blood samples are collected to assess cardiac biomarkers. Additionally, the hearts of all rats were separated and processed for histological evaluation, ultrastructural examination, and collagen content determination by Masson Triciumus staining, and biochemical studies. The DOX group had pronounced deleterious histological and ultrastructural disorganization accompanied with abundant collagen disposition. Biochemically, DOX group demonstrated significant elevation of cardiomyocytes content of MDA, NF-κB, TNF-α, IL-6, BAX, and TGF-β1 which mirrored as significantly elevated serum LDH, CKMB, and cTnI levels. However, SOD and CAT activities as well as GSH, BCL-2, SIRT3 and NRF2 content along with miRNA-133a gene expression are significantly decreased. Present results proved the prophylactic ALO antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic influence on the DOX-induced cardiotoxicity with proposed mechanisms entailing the activation of SIRT3 pathway that may be governed by miRNA-133a. However, these results are limited by the inspection lack of echocardiography or hemodynamic alterations, gain and loss of function, caspase activation, and mitochondrial health tests. Thus, ALO has the potential to be an appropriate therapy for DOX-induced cardiotoxicity.
N. F. Elmongy, Mohamed Ali Abbas, S. Elshora et al.· Tissue & Cell· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
